Lower respiratory tract infections are according to the World Health Organisation (WHO) the leading cause of deaths in lower and middle income countries and the third cause of death in the world. Lower respiratory tract infections are prevalent in young children under five and the elderly, and can lead to complications such as emphysema, lung abscess, bronchiolitis obliterans, acute respiratory distress syndrome and sepsis putting a huge financial burden on the health system worldwide.
There are a number of acute and chronic infections that can affect the lower respiratory tract. The two most common infections are bronchitis and pneumonia. Bronchitis is typically caused by viruses, and to a lesser extent by bacteria that infect the epithelium of the bronchi causing inflammation. Pneumonia is described as inflammation of the lung alveoli, leading to chest pain, fever and difficulty breathing. Pneumonia is typically caused by bacteria and viruses and can also be caused by fungi and other microorganism. The bacterium Streptococcus pneumonia, is one of the most common causes of pneumonia, and others include Haemophillus influenza, Chlamydophila pneumonia or Mycoplasma pneumonia. Around one third of infections are caused by viruses as for example rhinoviruses, coronaviruses, influenza virus, adenovirus or respiratory syncytial virus.
Bronchitis and pneumonia are typically diagnosed using various tests including physical examination, X-rays, sputum culture or pulmonary function tests. The treatment of bronchitis and pneumonia is depended on the causative agent. Bacteria can be widely treated with antibiotic. However, inappropriate use of antibiotics has resulted in strains with multiple antibiotic resistances. Viral Pneumonia can be treated with antiviral medication. Nevertheless, the effectiveness of such medication is dependent on the virus type and on the general health of the patient. Moreover, the use of antivirals can be problematic as they can cause severe side effects. Treatment of damaged lung tissue includes the use of anti-inflammatory agents, which can also be difficult as they are commonly known to suppress immune function which again can have serious consequences leading to secondary infections.
The angiopoietin-like proteins (ANGPTL 1-7) belong to a superfamily of angiogenic-regulating, secreted proteins that bear the highest similarity to members of the angiopoietin (Ang) family. Angptl4 has been recognized as a central player in various aspects of energy homoeostasis, and was found to be involved in wound healing, modulation of vascular permeability and the regulation of reactive oxygen species promoting tumourigenesis. None of the ANGPTL proteins binds to TIE 1/2 tyrosine kinase receptors, suggesting that they may exert distinct functions from the other ANG-proteins.
Like other members of this family, Angptl4 contains a secretory signal peptide, a predicted N-terminal coiled-coil quaternary structure and a large, C-terminal fibrinogen-like domain. The N-terminal region of Angptl4 (nAngptl4) is responsible for assembly into oligomeric structures which is important for its function as a lipoprotein lipase inhibitor. Full-length Angptl4 undergoes proteolytic processing at a linker region, thereby releasing nAngptl4 and the monomeric C-terminal portion of Angptl4 (cAngptl4). The cAngptl4 interacts with integrins β1/5, VE-cadherin and claudin-5 to stimulate intracellular signalling that aid wound healing. Expression of ANGPTL4 can be induced by numerous stimuli, such as glucocorticoid, TGFβ, nuclear hormone receptor PPARs and HIF-alpha.
Increased levels of Angptl4 have been measured in many human tumours, for example, renal carcinomas, oral tongue squamous cell carcinomas and human gastric cancers, and expression increased as tumours progress from benign to metastatic states. Studies suggest an involvement of Angptl4 in tumour growth and play a role through lymphovascular invasion. Patent application US2011311524 and US2006093607 discloses Angptl4 inhibitors and modulators for the treatment of cancer and other pathological conditions.
The use of antibodies as a tool for therapy is gaining increased popularity. Antibodies can be used to prevent tumour growth or to treat hormone imbalance by blocking specific receptors. Antibodies are also used in radioimmuno therapy to direct the radioactive compound to its specific target preserving healthy tissue. Humanized monoclonal antibodies are being used for the treatment of autoimmune diseases as different types of arthritis or Crohn's disease by blocking Tumour Necrosis Factor-alpha, a cytokine involved in systemic inflammation.
The authors have surprisingly found that cAngptl4 levels are significantly increased in damaged lung tissue following a bacterial or viral pneumonia infection. Moreover, anti-cAngptl4 monoclonal antibodies are shown to facilitate repair of damaged lung tissue.
The present disclosure relates to the use of cAngptl4 as diagnostic marker to diagnose acute lung damage caused by viral or bacterial infection and including cAngptl4 specific antibodies and their use in the treatment of viral or bacterial pneumonia.